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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2948_Библиотеки_им_академика_М_И_Перельмана
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382
It is my impression that immune-tolerant chronic hepatitis B refers to the
fact that the immune system does not recognize the hepatitis B virus as a for-
eign invader. This is a unique situation where the virus keeps replicating,
undisturbed by the immune system, and you can have hundreds of thousands,
or even millions of viral particles present with totally normal liver enzymes. If
you were to do a liver biopsy, there would be no signs of liver damage. Is that
correct?
This is the expected nding. The immune-tolerant phase of chronic HBV is
thought to be the result of reduced responsiveness of immunologic T cells to the
virus, which leads to unrestricted hepatitis B viral replication and, thus, high HBV
DNA viral load. Liver injury in chronic hepatitis B is the result of immune-mediated
(e.g., cytotoxic T cells, NK cells, and neutrophils) cell and tissue injury. Therefore,
a hypoactive immune response also means that there is little to no liver injury, which
explains the typically normal transaminases in immune-tolerant chronic hepatitis B.
Would you start antiviral therapy?
AASLD [1] and EASL [2] do not recommend starting antiviral treatment in
immune- tolerant chronic hepatitis B infection, unless the patient has any of the
following:
1. Cirrhosis
2. Extrahepatic manifestations (usually immune-mediated) of HBV infection such
as vasculitis, purpura, polyarteritis nodosa, arthralgias, neuropathy, and
glomerulonephritis
3. Receiving immunosuppressive therapy
4. Pregnant women with HBV DNA >200,000IU/mL in the third trimester to help
prevent mother-to-child transmission of HBV (tenofovir disoproxil fumarate is
the preferred antiviral medicine in pregnancy)
We are not starting antiviral therapy. How would you monitor this patient
after this initial encounter?
In these patients, liver chemistries and HBV DNA should be monitored every
3–6months to determine if they are transitioning to the immune-active or chronic
inactive phases of infection. Increasing transaminases warrants more frequent mon-
itoring. Patients should meet criteria for immune-active chronic hepatitis B (ALT
>2×ULN and HBV DNA >20,000IU/mL if HBeAg-positive and>2000 if HBeAg-
negative) for at least 3–6months before committing to antiviral therapy, since it is
possible that increased immunologic activity may lead to viral clearance and entry
into the chronic inactive phase of infection.
Some patients will have elevated transaminases that are less than 2× the upper
limit of normal. In addition to further testing to ensure that they do not have other
causes of liver disease, such as metabolic dysfunction or alcohol-associated fatty
liver diseases, liver biopsy and/or elastography should be considered for these
patients because signicant inammation or brosis will warrant antiviral therapy.
What other issues need to be addressed for this patient?
Certain subpopulations of patients with chronic hepatitis B should undergo
regular screening for hepatocellular carcinoma (HCC) with abdominal imaging
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(e.g., ultrasound, CT or MRI) and a-fetoprotein every 6months. Subpopulations
who should undergo regular HCC screening are:
1. All patients with cirrhosis
2. Asian and Black men above 40years old, irrespective of cirrhosis
3. Asian women above 50years old, irrespective of cirrhosis
4. First-degree relatives with HCC, irrespective of cirrhosis
Patients with immune-tolerant chronic hepatitis B are highly viremic and are
therefore very contagious. Sexual partners and household members of the patient
should be screened for chronic hepatitis B with HBsAg and anti-HBs testing.
Uninfected and nonimmune sexual partners and household members should com-
plete the hepatitis B vaccine series, followed by repeat anti-HBs testing to ensure an
adequate response to the vaccine.
The patient should also be counseled the following:
1. Use barrier contraception if their sexual partner is not vaccinated or naturally
immunized
2. Not to share toothbrushes and razors
3. Not to share injection equipment, including glucose testing equipment for
diabetics
4. Cover all open cuts and scratches
5. Clean blood spills with bleach solution
6. Not to donate blood, organs, or sperm
Is there a certain age when you would start antivirals in a patient with
immune-tolerant phase chronic hepatitis B?
AASLD [1] recommends liver biopsy in patients with immune-tolerant chronic
hepatitis B aged 40years and above, especially those infected at a young age and
with very elevated HBV viral load (HBV DNA>1 million IU/mL) to assess severity
of inammation and brosis. Immune-tolerant hepatitis B patients with at least
moderate inammation and/or stage 2 brosis should receive antiviral therapy.
These patients could alternatively undergo noninvasive testing of hepatic brosis
through elastography rst. Patients with signicant brosis (i.e., F2 or greater) on
elastography should warrant antiviral therapy.
EASL [2] is more aggressive and recommends antiviral therapy in patients with
immune-tolerant hepatitis B age 30years and above, regardless of the severity of
liver histologic lesions.
References
1. Terrault N, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, etal. Update on pre-
vention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.
Hepatology. 2018;67(4):1560–99.
2. European Association for the Study of the Liver. EASL 2017 clinical practice guidelines on the
management of hepatitis B virus infection. J Hepatol. 2017;67(2):370–98.
90 Immune-Tolerant Chronic HBV
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385© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
W. H. Sobin et al. (eds.), Managing Complex Cases in Gastroenterology,
https://doi.org/10.1007/978-3-031-48949-5_91
Chapter 91
Immune-Active Chronic HBV
JamesEsteban
A 30-year-old Asian male has had a diagnosis of chronic hepatitis B since his teen
years. His mother also has chronic hepatitis B.He previously had normal transami-
nases, HBV viral load ranging from 10 to 20million IU/mL, and positive HBeAg.
On routine testing 3months ago, he was found to have elevated transaminases (ALT
of 140, AST of 80). His HBV DNA remains elevated, but at a lower level than previ-
ously, currently at around 100,000IU/mL.On repeat testing today, he continues to
have elevated transaminases (ALT of 120, AST of 80) and elevated HBV DNA
(90,000IU/mL). He remains HBeAg-positive.
The fact that his liver chemistries increased to more than twice the upper
limit normal while maintaining signicant hepatitis B viremia indicates that
he has evolved into immune-active chronic hepatitis B.Can you explain the
signicance of the positive HBeAg and the usual transition to nega-
tive HBeAg?
The hepatitis B envelope antigen (HBeAg) is a hepatitis B viral protein that
indicates active viral replication. Thus, patients who are HBeAg-positive typically
have very high titers of HBV DNA in serum. HBeAg-positive infection, particu-
larly in younger persons, will have normal or near-normal transaminases, because
HBV does not have a direct cytopathic effect and does not cause liver inammation
on its own. This is known as the immune-tolerant phase of chronic hepatitis B
infection, where the body’s T-cell-mediated response to the virus is thought to be
blunted.
J. Esteban (*)
Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: jesteban@mcw.edu
https://t.me/medicina_free
386
The body may attempt to clear the virus at some point through an immune-
mediated and inammatory response, which leads to hepatic injury and inamma-
tion, causing a rise in transaminases and eventually hepatic brosis if left unabated.
HBV DNA titers remain elevated, but typically not at the same magnitude as in the
immune-tolerant phase. This is known as the immune-active phase of chronic hepa-
titis B infection.
The immune-active phase of chronic hepatitis infection is dened by the
AASLD as [1]:
1. HBsAg-positive for at least 6months
2. ALT or AST>2× upper limit of normal, dened as 35U/L in males and 25U/L
in females
3. HBV DNA >20,000IU/mL in HBeAg-positive hepatitis B and >2000IU/mL in
HBeAg-negative hepatitis B
The immune-active phase can lead to a couple of possible outcomes. The patient
can continue to have viral replication (HBeAg-positive, high HBV DNA) with con-
tinuing liver injury and inammation, and this warrants antiviral therapy. On the
other hand, the immune system may succeed in suppressing the infection, which
can lead to loss of HBeAg and low HBV DNA viral loads (dened as <2000 IU/
mL), indicating suppression of viral replication and improving liver chemistries.
This is known as the inactive phase of chronic hepatitis B infection. Spontaneous
HBeAg seroconversion, which is a way of saying that HBeAg is lost and anti-HBe
antibodies have appeared, occurs in 15% of cases per year [2]. Some patients may
lose hepatitis B surface antigen (HBsAg) altogether, representing a functional cure
of the infection, but this occurs much more rarely at a rate of 1–2% per year [3].
A few patients will have lost HBeAg but will continue to have active viral repli-
cation (i.e., high HBV DNA) and hepatic inammation (i.e., ALT >2× ULN). These
patients have HBeAg-negative, immune-active chronic hepatitis B, and typically
mutations in the precore or basal core promoter region of the HBV genome.
You decide that the patient has immune-active chronic hepatitis B and will
need antiviral therapy. What are the options and what would you recommend
for the patient?
AASLD [1] and EASL [4] recommend antiviral therapy in patients with immune-
active hepatitis B (Fig.91.1). (Note: “Chronic hepatitis B” is the EASL nomenclature
for immune-active hepatitis B, while “chronic HBV infection” is the EASL nomen-
clature for immune-tolerant hepatitis B) Antiviral therapy is also recommended in all
patients with cirrhosis and in patients who have signicant inammation or brosis
on liver biopsy or elastography, regardless of ALT and HBV DNA titers.
Patients who have elevated transaminases, but do not quite meet criteria for
immune-active hepatitis B, should undergo further evaluation for other liver dis-
eases. They should also be considered for liver biopsy or elastography. The presence
of signicant hepatic inammation and brosis stage 2 or greater warrants antiviral
treatment. Antiviral therapy is not recommended in most patients with immune-
tolerant hepatitis B, and this is discussed in a separate chapter.
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a
b
Fig. 91.1 Treatment algorithm for chronic hepatitis B according to HBeAg status. (a) HBeAg-
positive. (b) HBeAg-negative
The two treatment options for chronic hepatitis B include pegylated interferon
(PEG-IFNa) and nucleos(t)ide analogs (NA). Earlier generation NAs (lamivudine,
telbivudine, adefovir) have a low genetic barrier to resistance. Newer NAs (enteca-
vir, tenofovir disoproxil fumarate [TDF], tenofovir alafenamide [TAF]) have high
genetic barriers to resistance and are the recommended rst-line antiviral therapy
for chronic hepatitis B.In all honesty, we can choose either entecavir, TDF, or TAF
for our patient.
PEG-IFNa has the advantages of nite treatment duration (48weeks) and slightly
higher rates of HBsAg loss, but signicant side effects limit its wider use in clinical
practice, relative to entecavir and tenofovir. PEG-IFNa is contraindicated in decom-
pensated cirrhosis and acute liver failure.
91 Immune-Active Chronic HBV
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388
The patient has normal kidney function. He underwent vibration-controlled tran-
sient elastography (VCTE or FibroScan
®
), which showed liver stiffness of 5kPa
(F0). You recommend starting the patient on tenofovir disoproxil fumarate (TDF)
400mg once daily.
The patient asks about the effectiveness of TDF and possible long-term side
effects.
The effectiveness of TDF and other NAs in clinical trials are summarized
below [4]:
Entecavir TDF TAF
HBeAg-positive
Anti-HBe seroconversion 21% 21% 10%
HBV DNA suppression 67% 76% 64%
ALT normalization 68% 68% 72%
HBsAg loss 2% 3% 1%
HBeAg-negative
Anti-HBe seroconversion N/A N/A N/A
HBV DNA suppression 90% 93% 94%
ALT normalization 78% 76% 83%
HBsAg loss 0% 0% 0%
Long-term treatment with NA, specically due to result of suppression of viral
replication, halts the progression of liver disease, improves hepatic brosis (poten-
tially even regression of cirrhosis) and hepatic recompensation in cases of decom-
pensated cirrhosis, reduces the need for liver transplantation, and reduces the risk of
HCC [5].
TDF has been associated with renal dysfunction, including Fanconi syndrome,
and bone mineral density loss. Entecavir or TAF are preferred in older patients (age
>60years), patients with established osteopenia or osteoporosis or at risk for these
conditions (e.g., long-term use of corticosteroids), and patients with renal dysfunc-
tion (e.g., estimated GFR <60mL/min/1.73m
2
, established albuminuria).
After 9months on TDF, he becomes HBeAg-negative and develops anti-HBe. His
transaminases normalize and HBV DNA becomes undetectable.
Would you consider stopping TDF in this patient now or in the near future?
I would have him continue TDF for an additional 12months as consolidation
therapy. If transaminases remain normal and HBV DNA remain undetectable at the
end of consolidation therapy—assuming repeat VCTE or FibroScan
®
continues to
show absence of signicant brosis, he does not have extrahepatic manifestations,
and he is not receiving immunosuppressive therapy of any kind—then, yes, I will
consider discontinuing TDF. I would obtain transaminases and HBV DNA every
3months for at least a year to make sure that he does not experience a relapse and
hepatitis are-up.
The majority of initially HBeAg-positive patients who seroconvert remain in
remission [6]. Treatment discontinuation is discussed in more detail in another
chapter.
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389
References
1. Terrault N, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, etal. Update on pre-
vention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.
Hepatology. 2018;67(4):1560–99.
2. Dusheiko G, Agarwal KM, Maini MK.New approaches to chronic hepatitis B.N Engl J Med.
2023;388(1):55–69.
3. Yeo YH, Ho HJ, Yang HI, Tseng TC, Hosaka T, Trinh HY, etal. Factors associated with rates
of HBsAg Seroclearance in adults with chronic HBV infection: a systematic review and meta-
analysis. Gastroenterology. 2019;156(3):635–646.e9.
4. European Association for the Study of the Liver. EASL 2017 clinical practice guidelines on the
management of hepatitis B virus infection. J Hepatol. 2017;67(2):370–98.
5. Su TH, Hu TH, Chen CY, Huang YH, Chuang WL, Lin CC, etal. Four-year entecavir therapy
reduces hepatocellular carcinoma, cirrhotic events and mortality in chronic hepatitis B patients.
Liver Int. 2016;36(12):1755–64.
6. Papatheodoridis G, Vlachogiannakos I, Cholongitas E, Wursthorn K, Thomadakis C, Touloumi
G, et al. Discontinuation of oral antivirals in chronic hepatitis B: a systematic review.
Hepatology. 2016;63(5):1481–92.
91 Immune-Active Chronic HBV
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Chapter 92
HBV Treatment Discontinuation
JamesEsteban
A 42-year-old former IV heroin user with immune-active, HBeAg-positive, chronic
hepatitis B was treated with tenofovir disoproxil fumarate (TDF). After 6months of
treatment, he had normal liver chemistries and undetectable HBV DNA.He was still
HBeAg-positive. Shortly after, he ran out of TDF and went about 6months without
medication before returning to the ofce with malaise, jaundice, and right upper
quadrant tenderness. His current labs are ALT of 350, AST of 240, total bilirubin of
4mg/dL, and HBV DNA of 25million IU/mL.He continues to be HBeAg-positive.
Are patients with chronic hepatitis B able to come off antiviral therapy
without risk of relapse?
It is clear that our patient relapsed after treatment interruption of tenofovir.
Patients who are HBeAg-positive can potentially stop nucleos(t)ide analog (NA)
therapy after a nite duration of treatment. HBeAg-positive chronic hepatitis B
patients being considered for treatment discontinuation should, at minimum, have
achieved HBeAg seroconversion (i.e., HBeAg loss with appearance of anti-HBe),
normal liver chemistries, and undetectable HBV DNA.They should then continue
NA therapy for an additional 12 months (consolidation therapy) before NA
discontinuation.
Liver chemistries, HBV DNA, and signs and symptoms of hepatic decompensa-
tion should be followed very closely (i.e., every 3months) for the rst year after
treatment discontinuation. Available data indicate that, at 12months after treatment
discontinuation, initially HBeAg-positive patients will remain in virologic remis-
sion, biochemical remission, and HBeAg-negative in 60%, 75%, and 90% of cases,
respectively [1].
J. Esteban (*)
Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: jesteban@mcw.edu
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
W. H. Sobin et al. (eds.), Managing Complex Cases in Gastroenterology,
https://doi.org/10.1007/978-3-031-48949-5_92
https://t.me/medicina_free
392
The AASLD recommends that patients who are HBeAg-negative should remain
on NA therapy indenitely or until HBsAg is lost, based on data indicating high
rates of virologic (60%) and biochemical (45%) relapse [1, 2]. However, there is
evidence that NA therapy can be safely discontinued in select HBeAg-negative
patients with reasonably low risk of virologic relapse and hepatitis are, especially
if patients have undetectable HBV DNA for at least 2–3years while on treatment [1,
3]. As with HBeAg-positive patients, these patients should undergo frequent moni-
toring after stopping NA therapy. Interestingly, HBeAg-negative patients who stop
NA therapy may have a greater chance for HBsAg loss (up to 30%) if quantitative
HBsAg titers are <1000IU/mL at treatment discontinuation [4, 5]. Unfortunately,
quantitative HBsAg testing is not widely available in the United States.
Patients with cirrhosis, irrespective of HBeAg status, should remain on antiviral
treatment indenitely due to increased risk of fatal acute-on-chronic liver failure.
How would you manage this situation? Do you restart the same antiviral or
do you need to start something different because of concerns about resistance?
Since he continues to have immune-active, HBeAg-positive, chronic hepatitis B,
I will retreat and resume tenofovir. Entecavir and tenofovir are NAs with high
genetic barriers to resistance, and reported antiviral resistance to these agents is
uncommon (1% or less) [6]. The likelihood of resistance is proportionate to the
duration of treatment, and our patient has only been on treatment for a few months.
Antiviral-resistant viruses are in general also “less t” for replication than their
wild-type counterparts.
If he develops virological failure to tenofovir, dened as less than tenfold reduc-
tion in HBV DNA at 3months of treatment, or virological breakthrough, dened as
tenfold or more increase from the lowest HBV DNA level, then I would rst ascer-
tain that he is adhering to treatment. I will obtain HBV genotype and antiviral resis-
tance testing only after I am able to determine that he is adherent.
Switching to entecavir is the next step if he is tenofovir-resistant. Conversely,
switching to tenofovir is the next step if a patient is entecavir-resistant. Entecavir
should not be used if a patient is resistant to lamivudine or telbivudine. Combination
therapy with entecavir and tenofovir is typically not needed, since the individual
agents are highly effective on their own, but should be considered in cases of docu-
mented multidrug resistance or persistent plateauing viremia after 12 months or
more of treatment.
If our patient was HBeAg-negative at the start of NA treatment, how would
you manage the situation?
Experts recommend delaying retreatment of relapse in HBeAg-negative patients
for as long as possible, because this potentially increases the likelihood of spontane-
ously losing HBsAg and achieving functional cure [4, 5, 7]. These patients should
be followed up very closely. Some indications for retreatment include severe (e.g.,
ALT >10× ULN for more than 1week) or persistent (e.g., ALT >2× ULN for more
than 3months) hepatitis are or jaundice [5, 7]. My choice of NA therapy and deci-
sion to pursue antiviral resistance testing would be similar to HBeAg-positive
patients.
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References
1. Papatheodoridis G, Vlachogiannakos I, Cholongitas E, Wursthorn K, Thomadakis C, Touloumi
G, et al. Discontinuation of oral antivirals in chronic hepatitis B: a systematic review.
Hepatology. 2016;63(5):1481–92.
2. Terrault N, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, etal. Update on pre-
vention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.
Hepatology. 2018;67(4):1560–99.
3. European Association for the Study of the Liver. EASL 2017 clinical practice guidelines on the
management of hepatitis B virus infection. J Hepatol. 2017;67(2):370–98.
4. van Bömmel F, Berg T.Risks and benets of discontinuation of nucleos(t)ide analogue treat-
ment: a treatment concept for patients with HBeAg-negative chronic hepatitis B. Hepatol
Commun. 2021;5(1):1632–48.
5. van Bömmel F, Stein K, Heyne R, Petersen J, Buggisch P, Berg C, et al. A multicenter
randomized- controlled trial of nucleos(t)ide analogue cessation in HBeAg-negative chronic
hepatitis B.J Hepatol. 2023;78(5):926–36.
6. Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J, et al. Long-term
monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare
through 5 years of therapy. Hepatology. 2009;49(5):1503–14.
7. Hadziyannis SJ, Sevastianos V, Rapti I, Vassilopoulos D, Hadziyannis E.Sustained responses
and loss of HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term
treatment with Adefovir. Gastroenterology. 2012;143(3):629–36.
92 HBV Treatment Discontinuation
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